scholarly journals Structural elucidation of innate immune signaling

2014 ◽  
Vol 70 (a1) ◽  
pp. C298-C298
Author(s):  
Hao Wu
Keyword(s):  
Signal Transduction ◽  
Interleukin 1 ◽  
Structural Elucidation ◽  
Innate Immune ◽  
Structural Studies ◽  
Toll Like Receptor ◽  
Immune Signaling ◽  
Kinase Activation ◽  
Innate Immune Signaling

Signal transduction in the Toll-like receptor and interleukin-1 receptor pathways requires both kinase activation and ubiquitination. Here, we will present our recent structural studies on critical mediators of the pathways.

Interactions between Viperin, IRAK1 andTRAF6 couple innate immune signaling to antiviral ribonucleotide synthesis

2018 ◽  
Author(s):  
Arti B. Dumbrepatil ◽  
Soumi Ghosh ◽  
Ayesha M. Patel ◽  
Kelcie A. Zegalia ◽  
Paige A. Malec ◽  
...  
Keyword(s):  
Structural Changes ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Tnf Receptor ◽  
Toll Like Receptor ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Synergistic Activation ◽  
Catalytically Active ◽  
Cellular Antiviral Response

SummaryViperin is a radical S-adenosylmethionine (SAM) enzyme that plays a multifaceted role in the cellular antiviral response. Viperin was recently shown to catalyze the SAM-dependent formation of 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP), which inhibits some viral RNA polymerases. Viperin is also implicated in regulating K63-linked poly-ubiquitination of interleukin-1 receptor-associated kinase-1 (IRAK1) by the E3 ubiquitin ligase TNF Receptor-Associated Factor 6 (TRAF6) as part of the Toll-like receptor-7 and 9 (TLR7/9) innate immune signaling pathways. We show that IRAK1 and TRAF6 activate viperin to efficiently catalyze the radical-mediated dehydration of CTP to ddhCTP. Furthermore, poly-ubiquitination of IRAK1 requires the association of viperin with IRAK1 and TRAF6. Poly-ubiquitination appears dependent on structural changes induced by SAM binding to viperin but does not require catalytically active viperin. The synergistic activation of viperin and IRAK1 provides a mechanism that couples innate immune signaling with the production of the antiviral nucleotide ddhCTP.

scholarly journals MAVS: A Two-Sided CARD Mediating Antiviral Innate Immune Signaling and Regulating Immune Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunqiang Chen ◽  
Yuheng Shi ◽  
Jing Wu ◽  
Nan Qi
Keyword(s):  
Signal Transduction ◽  
Innate Immune ◽  
Immune Homeostasis ◽  
Type I ◽  
Interferon Signaling ◽  
Immune Signaling ◽  
Post Translational Modifications ◽  
Innate Immune Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

Mitochondrial antiviral signaling protein (MAVS) functions as a “switch” in the immune signal transduction against most RNA viruses. Upon viral infection, MAVS forms prion-like aggregates by receiving the cytosolic RNA sensor retinoic acid-inducible gene I-activated signaling and further activates/switches on the type I interferon signaling. While under resting state, MAVS is prevented from spontaneously aggregating to switch off the signal transduction and maintain immune homeostasis. Due to the dual role in antiviral signal transduction and immune homeostasis, MAVS has emerged as the central regulation target by both viruses and hosts. Recently, researchers show increasing interest in viral evasion strategies and immune homeostasis regulations targeting MAVS, especially focusing on the post-translational modifications of MAVS, such as ubiquitination and phosphorylation. This review summarizes the regulations of MAVS in antiviral innate immune signaling transduction and immune homeostasis maintenance.

scholarly journals Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors

2009 ◽  
Vol 15 (7) ◽  
pp. 997-1006 ◽  
Author(s):  
Masayuki Fukata ◽  
Yasmin Hernandez ◽  
Daisy Conduah ◽  
Jason Cohen ◽  
Anli Chen ◽  
...  
Keyword(s):  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Immune Signaling ◽  
Inflammatory Microenvironment ◽  
Innate Immune Signaling ◽  
Associated Tumors

All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction

2002 ◽  
Vol 115 (4) ◽  
pp. 679-688 ◽  
Author(s):  
Jee Y. Chung ◽  
Young Chul Park ◽  
Hong Ye ◽  
Hao Wu
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Functional Divergence ◽  
Interleukin 1 ◽  
Tnf Receptor ◽  
Structural Studies ◽  
Toll Like Receptor ◽  
Signal Transducers ◽  
Signaling Specificity ◽  
Necrosis Factor

The tumor necrosis factor (TNF) receptor associated factors (TRAFs) have emerged as the major signal transducers for the TNF receptor superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. TRAFs collectively play important functions in both adaptive and innate immunity. Recent functional and structural studies have revealed the individuality of each of the mammalian TRAFs and advanced our understanding of the underlying molecular mechanisms. Here, we examine this functional divergence among TRAFs from a perspective of both upstream and downstream TRAF signal transduction pathways and of signaling-dependent regulation of TRAF trafficking. We raise additional questions and propose hypotheses regarding the molecular basis of TRAF signaling specificity.

scholarly journals PI-5 Regulating Innate immune signaling using single immunoglobulin interleukin-1 regulated receptor protein

2019 ◽  
Vol 81 ◽  
pp. 78
Author(s):  
Mercedes Ferandes ◽  
Jahid Carr ◽  
Joseph Crnkovich ◽  
Shouq Alanezis ◽  
Yajing Wang ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Innate Immune ◽  
Receptor Protein ◽  
Immune Signaling ◽  
Innate Immune Signaling

scholarly journals Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6

2008 ◽  
Vol 205 (5) ◽  
pp. 1077-1086 ◽  
Author(s):  
Fabiana S. Machado ◽  
Lísia Esper ◽  
Alexandra Dias ◽  
Rajat Madan ◽  
YuanYuan Gu ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Proteasomal Degradation ◽  
Innate Immune ◽  
Cytokine Signaling ◽  
Immune Signaling ◽  
Innate Immune Signaling

Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2–dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor–associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinflammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These findings suggest a new molecular target for drug development for diseases marked by dysregulated inflammatory responses.

scholarly journals Viral Double-Strand RNA-Binding Proteins Can Enhance Innate Immune Signaling by Toll-Like Receptor 3

PLoS ONE ◽  
2011 ◽  
Vol 6 (10) ◽  
pp. e25837 ◽  
Author(s):  
Yvonne Lai ◽  
Guanghui Yi ◽  
Alice Chen ◽  
Kanchan Bhardwaj ◽  
Brady J. Tragesser ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Immune Signaling ◽  
Innate Immune Signaling

scholarly journals Hexa-Acylated Lipid A Is Required for Host Inflammatory Response to Neisseria gonorrhoeae in Experimental Gonorrhea

2013 ◽  
Vol 82 (1) ◽  
pp. 184-192 ◽  
Author(s):  
Xiyou Zhou ◽  
Xi Gao ◽  
Peter M. Broglie ◽  
Chahnaz Kebaier ◽  
James E. Anderson ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Lipid A ◽  
Innate Immune ◽  
Immune Recognition ◽  
Toll Like Receptor ◽  
Inflammatory Signaling ◽  
Toll Like Receptor 4 ◽  
Immune Signaling ◽  
Content Type ◽  
Innate Immune Signaling

ABSTRACTNeisseria gonorrhoeaecauses gonorrhea, a sexually transmitted infection characterized by inflammation of the cervix or urethra. However, a significant subset of patients withN. gonorrhoeaeremain asymptomatic, without evidence of localized inflammation. Inflammatory responses toN. gonorrhoeaeare generated by host innate immune recognition ofN. gonorrhoeaeby several innate immune signaling pathways, including lipooligosaccharide (LOS) and other pathogen-derived molecules through activation of innate immune signaling systems, including toll-like receptor 4 (TLR4) and the interleukin-1β (IL-1β) processing complex known as the inflammasome. The lipooligosaccharide ofN. gonorrhoeaehas a hexa-acylated lipid A.N. gonorrhoeaestrains that carry an inactivatedmsbB(also known aslpxL1) gene produce a penta-acylated lipid A and exhibit reduced biofilm formation, survival in epithelial cells, and induction of epithelial cell inflammatory signaling. We now show thatmsbB-deficientN. gonorrhoeaeinduces less inflammatory signaling in human monocytic cell lines and murine macrophages than the parent organism. The penta-acylated LOS exhibits reduced toll-like receptor 4 signaling but does not affectN. gonorrhoeae-mediated activation of the inflammasome. We demonstrate thatN. gonorrhoeaemsbBis dispensable for initiating and maintaining infection in a murine model of gonorrhea. Interestingly, infection withmsbB-deficientN. gonorrhoeaeis associated with less localized inflammation. Combined, these data suggest that TLR4-mediated recognition ofN. gonorrhoeaeLOS plays an important role in the pathogenesis of symptomatic gonorrhea infection and that alterations in lipid A biosynthesis may play a role in determining symptomatic and asymptomatic infections.

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